The site of anti‐arthritic action of the K‐opioid, U‐50,488H, in adjuvant arthritis: importance of local administration

Abstract

. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (K)‐opioid, U‐50,488H (trans‐(±)‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl) cyclohexyl]‐benzene‐acetamide methane sulphonate), possesses anti‐arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, K‐opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti‐arthritic effects in the periphery. Thus, the dose‐effect relationship of a K‐opioid agonist, U‐50,488H was compared after both local and distant administration. Further, we tested whether the anti‐arthritic effects of this drug are stereospecific and receptor‐mediated by use of opioid antagonists. . Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (±)‐U‐50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (±)‐U‐50,488H on radiology and histology varied according to treatment time. Administration of (±)‐U‐50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (±)‐U‐50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose‐dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (±)‐U‐50,488H was approximately fourfold more potent as an ‘anti‐arthritic’ agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 ± 1.6 vs 19.5 ± 0.8 mg kg−1). . Equivalent doses of the (−)−enantiomer (20 mg kg−1 day−1) and the racemate (±) of U‐50,488H (40 mg kg−1 day−1), elicited a similar attenuation of arthritic parameters while the (+)‐enantiomer exacerbated arthritis, suggesting that the anti‐arthritic activity lies solely with the (−)−enantiomer. . Both the peripherally selective antagonist, naloxone methiodide, and the K‐selective antagonist, MR2266 ((−)−5, 9α‐diethyl‐2‐(3‐furylmethyl)‐2′‐hydroxy‐6,7‐benzomorphan), were able to reverse fully the peripheral anti‐arthritic effects of U‐50,488H, indicating that it exerts its effects through peripheral K‐opioid receptors. . Taken together, these results not only confirm our previous findings that demonstrate anti‐arthritic effects of U‐50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral K‐receptors in the arthritic joint. Peripherally acting K‐opioid agonists should lead to new therapies for arthritis.

Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats

“…The antagonist study confirmed that this local anti-nociception was in the tail and was mediated by different opioid receptors. These results support the notion that activation of peripheral opioid receptors can relieve nociception mediated by different mechanisms (Stein et al 1989;Stein 1995;Nagasaka et al 1996;Wilson et al 1996;Ko et al 1998Ko et al , 1999.…”

“…More interestingly, when small, systemically inactive doses of mu or kappa opioid agonists were co-administered with capsaicin in the tail, they locally attenuated nociceptive responses (Ko et al 1998(Ko et al , 1999. These observations strengthen the notion that peripheral antinociception can be achieved by local administration of opioids into the injured tissue without producing central side effects (Stein 1995;Wilson et al 1996).…”

“…It has been shown that locally administered opioid agonists produce antinociceptive effects by interacting with peripheral opioid receptors in inflamed tissues (Stein et al 1989;Nagasaka et al 1996;Wilson et al 1996). This discovery has stimulated research into treatments that minimize central side effects.…”

Involvement of Interleukin‐1β in Systemic Morphine Effects on Paw Oedema in a Mouse Model of Acute Inflammation

“…Immune cells have been shown to contain and release opioid peptides, and immunosuppressive agents can inhibit these effects [1]. Upregulation of opioid receptors in the periphery during inflammation has been demonstrated [2]. However, the interaction between opioids and immune response is both complicated and significant [3].…”

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

“…Substantial evidence also described the peripheral mechanism of KOR agonists in mediating inflammation (238)(239)(240). KOR agonists have been proven previously as a powerful antiinflammatory therapy in a dose-dependent, time-dependent, stereo-selective and antagonist reversible manner during development of arthritis.…”